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RNA-binding motif protein RBM39 enhances the proliferation of gastric cancer cells by facilitating an oncogenic splicing switch in MRPL33

Acta Pharmacologica Sinica volume 46, pages 1068–1081 (2025)Cite this article

Abstract

Gastric cancer is a malignant gastrointestinal disease characterized by high morbidity and mortality rates worldwide. The occurrence and progression of gastric cancer are influenced by various factors, including the abnormal alternative splicing of key genes. Recently, RBM39 has emerged as a tumor biomarker that regulates alternative splicing in several types of cancer. However, the specific functions and key alternative splicing events modulated by RBM39 in gastric cancer are still unclear. In this work, bioinformatic analysis of The Cancer Genome Atlas (TCGA) database and immunoblotting of patient tissue samples revealed that RBM39 was highly expressed in gastric cancer tissues and that its elevated expression significantly reduced overall patient survival. Cell-line-based and tumor xenograft experiments demonstrated that RBM39 knockdown attenuated the growth of gastric cancer cells both in vitro and in vivo. Mechanistically, through RNA-seq, minigene, and RT‒PCR, we discovered and further validated that RBM39 inhibited exon 3 skipping, thereby modulating the splicing of MRPL33. The long isoform MRPL33-L, which includes exon 3, but not the short isoform MRPL33-S, which lacks exon 3, significantly promoted the proliferation and colony formation of gastric cancer cells. Furthermore, we observed an increased percent-splice-in (PSI) of MRPL33 in gastric cancer tissues. Genetic manipulation and pharmacological treatment with the RBM39 degrader indisulam demonstrated that RBM39 regulated cell proliferation by influencing the splicing switch of MRPL33 in gastric cancer cells and a xenograft mouse model. Our findings indicate that RBM39 regulates the oncogenic splicing of MRPL33 and suggest that it may serve as a potential therapeutic target for gastric cancer.

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Fig. 1: Increased expression of RBM39 in human gastric cancer tissues and its correlation with poor prognosis in gastric cancer patients.
Fig. 2: RBM39 promotes the growth of gastric cancer cells both in vitro and in vivo.
Fig. 3: RBM39 regulates alternative splicing.
Fig. 4: RBM39 regulates the exon 3 skipping of MRPL33.
Fig. 5: MRPL33-L regulates the proliferation and colony formation of gastric cancer cells.
Fig. 6: RBM39 modulates the proliferation of gastric cancer cells partially through the splicing of MRPL33.
Fig. 7: Indisulam inhibits the growth of gastric cancer cells and regulates the splicing of MRPL33 in vivo.
Fig. 8

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Acknowledgements

We would like to express our gratitude to Prof. Ying Feng at the Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, for generously providing the MRPL33 minigene plasmids. This work was supported by the National Natural Science Foundation of China (32171437), the National Key R&D Program of China (2019YFA0802401), the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (22KJB310017), Suzhou Science and Technology Development Project (SZM2023006), Gusu Key Health Talent Program of Suzhou (GSWS2022122), the Young Physician Scientists Program (ML42900323) and Interdisciplinary Basic Frontier Innovation Program (YXY2302015) at Suzhou Medical College of Soochow University, the National Center for International Research (2017B01012), the Jiangsu Key Laboratory of Neuropsychiatric Diseases (BM2013003), and a project funded by the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions.

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Authors and Affiliations

  1. Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, The Fourth Affiliated Hospital of Soochow University, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, 215123, China

    Cheng-piao Lu, Jia-bin Li, Xiao-gang Jiang & Guoqiang Xu

  2. Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China

    Dong-bao Li

  3. Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China

    Yu-hong Wang

  4. Department of Pharmacy, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Medical Center of Soochow University, Suzhou, 215123, China

    Jing-jing Ma & Guoqiang Xu

  5. Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China

    Guoqiang Xu

  6. MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, 215123, China

    Guoqiang Xu

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  1. Cheng-piao Lu
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Contributions

CPL, JBL, XGJ, JJM, and GX designed the research; CPL performed the research, DBL and YHW collected patient samples; CPL and GX analyzed the data and drafted the paper; all authors revised the paper.

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Correspondence to Xiao-gang Jiang, Jing-jing Ma or Guoqiang Xu.

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Lu, Cp., Li, Jb., Li, Db. et al. RNA-binding motif protein RBM39 enhances the proliferation of gastric cancer cells by facilitating an oncogenic splicing switch in MRPL33. Acta Pharmacol Sin 46, 1068–1081 (2025). https://doi.org/10.1038/s41401-024-01431-4

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